Elsevier

European Journal of Cancer

Volume 40, Issue 13, September 2004, Pages 1934-1940
European Journal of Cancer

The emerging role of reactive oxygen species in cancer therapy

https://doi.org/10.1016/j.ejca.2004.02.031Get rights and content

Abstract

The generation of reactive oxygen species (ROS) can be exploited therapeutically in the treatment of cancer. One of the first drugs to be developed that generates ROS was procarbazine. It is oxidised readily in an oxic environment to its azo derivative, generating ROS. Forty years ago, Berneis reported a synergistic effect in DNA degradation when procarbazine was combined with radiation; this was confirmed in preclinical in vivo modes. Early uncontrolled clinical trials suggested an enhancement of the radiation effect with procarbazine, but two randomised trials failed to confirm this. The role of ROS in cancer treatments and in the development of resistance to chemotherapy is now better understood. The possibility of exploiting ROS as a cancer treatment is re-emerging as a promising therapeutic option with the development of agents such as buthionine sulfoximine and motexafin gadolinium.

Section snippets

Buthionine sulfoximine

Buthionine sulfoximine (BSO) inhibits the rate-limiting enzyme in the synthesis of glutathione (GSH), γ-glutamylcysteine sythetase, which is often upregulated in chemotherapy-resistant tumours. The depletion of cellular GSH can restore sensitivity to the oxidative cytotoxic effect of platinum compounds and alkylators. For example, Bcl-2-overexpressing MCF-7 breast cancer cells have a nearly threefold increase in glutathione levels, rendering them resistant to cisplatin. Pretreatment with BSO

Motexafin gadolinium

Motexafin gadolinium is an expanded porphyrin that selectively localises in tumours. It has a multifunctional mechanism of action, including the generation of ROS and the depletion of reducing metabolites, such as protein thiols, thioredoxin, nicotinamide adenine dinucleotide phosphate (NADPH), ascorbate and glutathione [45]. Electrons are transferred from the reducing metabolites to oxygen to generate ROS (Fig. 3). The drug inhibits ATP production by interfering with electron transfer [46].

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